The incidence of sepsis is approximately 750,000 per year in the US with a mortality of 30 to 50% and an annual cost of $17 billion (Hotchkiss, R. S. and I. E. Karl, The pathophysiology and treatment of sepsis. N Engl J Med, 2003. 348(2): p. 138-50). When severe, sepsis is often associated with profound hypotension, massive vasodilation, shock, and multiple organ failure. Patients with sepsis commonly need general anesthesia for important therapeutic interventions such as intubation and surgery. Unfortunately, all general anesthetics produce serious and potentially life-threatening side effects, particularly in critically ill patients with sepsis. Of greatest concern is cardiovascular depression, which is produced by nearly all anesthetics.
Etomidate is a highly potent IV anesthetic that is distinguished from other general anesthetics by its ability to maintain cardiovascular stability. It induces loss of righting reflex in tadpoles (Husain, S. S., et al., 2-(3-Methyl-3H-diaziren-3-yl)ethyl 1-(1-phenylethyl)-1H-imidazole-5-carboxylate: a derivative of the stereoselective general anesthetic etomidate for photolabeling ligand-gated ion channels. J Med Chem, 2003. 46(7): p. 1257-65) and loss of responsiveness in humans (Arden, J. R., F. O. Holley, and D. R. Stanski, Increased sensitivity to etomidate in the elderly: initial distribution versus altered brain response. Anesthesiology, 1986. 65(1): p. 19-27) at a concentration of ˜2 μM. At the molecular level, there is compelling evidence that etomidate produces anesthesia by modulating the function of GABAA receptors (Jurd et al., Faseb J (2003) 17(2): 250-2 and Rusch et al., J Biol Chem (2004) 279(20): 20982-92). Etomidate enhances GABAA receptor-mediated currents evoked by low concentrations of GABA, but has little effect on currents evoked by high concentrations of GABA. This shifts the GABA concentration-response curve leftward, reducing the GABA EC50. This receptor mechanism is also thought to account for the anesthetic action of propofol.
There is a growing understanding of where etomidate acts on the GABAA receptor to produce anesthesia. Photoaffinity labeling studies have identified two amino acids in GABAA receptors that contribute to the etomidate binding site: Met-236 on the α subunit and Met-286 on β the subunit (Li et al., J Neurosci (2006) 26(45): 11599-605). Structural homology modeling of the GABAA receptor based on the Torpedo acetylcholine receptor structure strongly suggests that these two amino acids contribute to an anesthetic binding pocket located at the interface between α and β subunits. This conclusion is supported by mutagenesis studies showing that mutating these amino acids to a tryptophan attenuates the receptor's sensitivity to etomidate (Stewart et al., Mol Pharmacol (2008) 74(6): 1687-95).
Inhibition of steroid synthesis is a potentially deadly side effect of etomidate administration, particularly in critically ill patients, e.g., patients with sepsis, who might otherwise benefit most from its use. This inhibition is extremely potent, occurring at doses of etomidate that are below those which produce general anesthesia. It is also extremely dangerous as it significantly increases the mortality of critically ill patients who have received continuous etomidate infusions. For example, Watt, I. and I. M. Ledingham, Anaesthesia (1984) 39(10): 973-81, retrospectively found that critically ill trauma patients more commonly required vasopressors (p<0.0001) and had a mortality that was nearly 3-fold higher (77% vs. 28%; p<0.0005) when sedated with etomidate vs. benzodiazepines even after matching for age, gender, and injury severity score. Because of its effect on steroid synthesis, etomidate cannot be safely administered to critically ill patients as a prolonged continuous infusion and the administration of even a single IV bolus dose for anesthetic induction in septic patients has recently raised concerns. It has been suggested that such morbidity and mortality might be reduced by empirically administering exogenous steroids (Ray, D. C. and D. W. McKeown, Crit. Care (2007) 11(3): R56); however, this approach is suboptimal as the dosing, timing, and duration of steroid therapy in any given patient would be speculative. Furthermore, the administration of exogenous steroids can itself produce significant complications (particularly in the setting of sepsis) including altered glucose homeostasis, impaired wound healing, and immunosuppression. It has been suggested that these complications explain, at least in part, the results of the CORTICUS study indicating that while exogenous steroids reduce vasopressor requirements, they don't improve survival even in critically ill patients deemed to have adrenocortical insufficiency (Sprung et al., N Engl J Med (2008) 358(2): 111-24).
Etomidate suppresses adrenocortical steroid synthesis primarily by binding to and inhibiting 11βhydroxylase (i.e. CYP11B1), a cytochrome P450 enzyme that is necessary for the biosynthesis of cortisol, corticosterone, and aldosterone (de Jong et al., J Clin Endocrinol Metab (1984) 59(6): 1143-7). Etomidate's half-maximal inhibitory concentration (IC50) is in the low nanomolar range (Lamberts et al., J Pharmacol Exp Ther (1987) 240(1): 259-64 and Roumen et al., J Comput Aided Mol Des (2007) 21(8): 455-71), a concentration range that is orders of magnitude lower than its hypnotic/anesthetizing concentration.
Previous crystallographic studies of imidazole-containing drugs (e.g. ketoconazole) to various cytochrome P450 enzymes have shown that high affinity binding requires a strong attractive interaction (“coordination”) between the basic nitrogen in the drug's imidazole ring and the heme iron at the enzyme's catalytic site (Zhao et al., J Biol Chem (2006) 281(9): 5973-81; Podust et al., Proc Natl Acad Sci USA (2001) 98(6): 3068-73; and Verras et al, Protein Eng Des Sel (2006) 19(11): 491-6); cytochrome P450 enzymes (including 11β-hydroxylase) contain heme prosthetic groups at their catalytic sites. Although 11β-hydroxylase has not yet been crystallized nor its interaction with etomidate defined, homology modeling studies suggest that high affinity binding of etomidate to 11β-hydroxylase also requires coordination between the basic nitrogen in etomidate's imidazole ring and the enzyme's heme iron. This led to the prediction that high affinity binding to 11β-hydroxylase (and thus adrenolytic activity) could be “designed out” of etomidate (without disrupting potent anesthetic and GABAA receptor activities) by replacing this basic nitrogen with other chemical groups that cannot coordinate with heme iron. This would be highly desirable because it allows for potent anesthetic and GABAA receptor modulatory activities while not suppressing adrenocortical function at clinically relevant doses.
There is a great need for safer general anesthetics for use in critically ill patients, and particularly for patients with sepsis. (R)-Etomidate possesses many properties that would make it an ideal anesthetic agent (e.g. high anesthetic potency, lesser effects on cardiovascular function and higher therapeutic index than other agents) if it were not such a potent inhibitor of adrenocortical function.
Thus, there is a need in the art to develop analogues of (R)-etomidate that retain its many beneficial properties (e.g. rapid onset of action, little effect on blood pressure, high therapeutic index), but do not cause potentially dangerous inhibition of adrenocortical function. Such analogues will permit anesthesia to be administered more safely to patients who are critically ill. This invention answers that need.